Preoperative Intravitreal Bevacizumab Use as an Adjuvant to Diabetic Vitrectomy: Histopathologic Findings and Clinical Implications

El-Sabagh, Hazem A; Abdelghaffar, Walid; Labib, Ahmad M.; Mateo, Carlos; Hashem, Tarek; Al-Tamimi, Dalal M.; Selim, Abdulhafez

doi:10.1016/j.ophtha.2010.08.038

Cited by 69 publications

(56 citation statements)

References 18 publications

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“…32,33 Injection of anti-VEGF drugs could lead to a profibrotic switch with significant reduction in the neovascular component, as determined by decreased expression of the panendothelial marker CD34 and the marked increase in the contractile elements, smooth muscle actin and collagen, of the proliferative membrane over time. 33 These histologic findings provided evidence that EVP observed by OCT angiography might represent newly growing sections of active new vessels as they are significantly affected by VEGF inhibition. Conversely, pruned new vessels with no sign of EVP likely reflect the inactive fibrotic stage of neovascular membranes.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography

Ishibazawa

Nagaoka

Yokota

et al. 2016

Invest. Ophthalmol. Vis. Sci.

125

103

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PURPOSE.To characterize the morphology of neovascularization at the disc (NVD) and neovascularization elsewhere (NVE) in treatment-naïve or previously treated proliferative diabetic retinopathy (PDR) patients using optical coherence tomography (OCT) angiography. METHODS.En face OCT angiograms of NVD/NVE in 40 eyes of 33 patients with PDR were acquired using RTVue XR Avanti OCT. The morphology of NVD/NVE on OCT angiograms was evaluated, and the activity was determined by biomicroscopy and fluorescein angiography (FA). In 12 eyes that were treated or treatment-naïve, changes in the morphology and vessel area of NVD/NVE before and after panretinal photocoagulation (PRP) were investigated.RESULTS. Twenty eyes had treatment-naïve PDR, whereas 20 eyes were previously treated with PRP. All treatment-naïve NVD/NVE had remarkable (i.e., active) leakage in early-phase FA. Ninety-five percent of treatment-naïve NVD/NVE observed by OCT angiography had exuberant vascular proliferation (EVP), identified as irregular proliferation of fine (smallercaliber) new vessels; whereas, the presence of EVP in previously treated eyes (13/20) was significantly less than in treatment-naïve eyes (65% vs. 95%, P ¼ 0.043). The remaining seven treated eyes had pruned NVD/NVE without EVP, observed as fibrotic changes or faint (inactive) leakage in FA. The vessel areas of NVD/NVE significantly decreased following PRP (n ¼ 12, P ¼ 0.019), and NVD/NVE morphology showed pruning and decreased EVP.CONCLUSIONS. Exuberant vascular proliferation on OCT angiograms should be considered as an active sign of neovascularization; therefore, morphologic evaluation of neovascularization using OCT angiography may be useful to estimate the activity of each neovascularization in eyes with PDR.

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Section: Discussionmentioning

confidence: 99%

Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography

Ishibazawa

Nagaoka

Yokota

et al. 2016

Invest. Ophthalmol. Vis. Sci.

125

103

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“…Previous studies demonstrated the progression or development of TRD following IVB treatment [15, 16]. Research also described a profibrotic switch after IVB treatment that resulted in a noticeable reduction in neovascular components, and a marked increase in contractile elements of the proliferative membranes over time has been observed in diabetic fibrovascular proliferative membranes after IVB treatment [17]. Li et al [18] reported that bFGF levels increased after IVB treatment more than 14 days prior to surgery.…”

Section: Discussionmentioning

confidence: 99%

“…However, the etiology of these complications after IVB treatment remains unclear. Accumulating evidence suggests that IVB not only blocks VEGF but also causes changes in the levels of various cytokines in PDR, suggesting that the IVB-modulated cytokine profile affects the fibrovascular membrane (FVM) microenvironment [17]. A previous study showed that the timing of anti-VEGF therapy played an important role in the development of fibrosis, with longer lapses following IVB treatment resulting in increased levels of basic fibroblast growth factor (bFGF) [18].…”

Section: Introductionmentioning

confidence: 99%

Preoperative Timing of Intravitreal Bevacizumab Injection for Proliferative Diabetic Retinopathy Patients

Feng

Wen

et al. 2018

Ophthalmic Res

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Objective: To evaluate the changes in aqueous concentrations of inflammatory cytokines and fibrosis-related factors, and to detect the expression of vascular endothelial growth factor (VEGF) and proliferating cells in fibrovascular membranes (FVMs) of patients with proliferative diabetic retinopathy (PDR) after injection of intravitreal bevacizumab (IVB). Methods: Forty-two eyes of 42 patients with PDR, including 28 eyes that received IVB (1.25 mg) 2, 5, and 14 days before pars plana vitrectomy (PPV), and 14 eyes without IVB, were enrolled, in addition to 10 eyes of 10 patients with nondiabetic ocular diseases. Aqueous concentrations of inflammatory cytokines and fibrosis-related factors were analyzed by a multiplex bead assay. Fluorescence immunostaining was performed to examine the expression of VEGF and proliferating cells in the excised epiretinal membranes. Results: PDR eyes without IVB had the highest vitreous VEGF levels, and the level was statistically significant compared with that of PDR eyes that received IVB 2 days before surgery, PDR eyes that received IVB 5 days before surgery, and nondiabetic eyes (p = 0.011, p = 0.012, and p < 0.001, respectively). The expression of fibroblastic cells and connective tissue growth factor increased in epiretinal FVMs of the IVB group 21 days after treatment. Conclusions: IVB injection may lead to a decrease in the intraocular concentrations of VEGF after 2–5 days and induce the formation of proliferation after 21 days, which suggests that PPV in PDR patients should take place within 1 week of the administration of preoperative IVB.

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“…19 Also, a fibrotic switch has been observed in diabetic fibrovascular proliferative membranes after bevacizumab. 20 Our model suggests a critical balance between VEGF and CTGF as a determinant of the disease course in PDR, in particular the angiofibrotic switch. It predicts that a reduction in VEGF levels, by causing a shift in the CTGF/VEGF balance in favour of CTGF, leads to accelerated fibrosis.…”

mentioning

confidence: 80%

A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy

Schlingemann

Geest

Oberstein

et al. 2012

Acta Ophthalmologica

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Purpose In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) may cause blindness by neovascularisation followed by fibrosis of the retina. It has previously been shown that a shift in the balance between levels of CTGF and VEGF in the eye is associated with this angiofibrotic switch. This study investigated whether anti‐VEGF agents induce accelerated fibrosis in patients with PDR, as predicted by this model. Methods CTGF and VEGF levels were measured by ELISA in 52 vitreous samples of PDR patients, of which 24 patients had received intravitreal bevacizumab 1 week to 3 months before vitrectomy, and were correlated with the degree of vitreoretinal fibrosis as determined clinically and intra‐operatively. Results CTGF correlated positively, and VEGF correlated negatively with the degree of fibrosis. The CTGF/VEGF ratio was the strongest predictor of fibrosis. Clinically, increased fibrosis was observed after intravitreal bevacizumab. Conclusion These results confirm that the CTGF/VEGF ratio is a strong predictor of vitreoretinal fibrosis in PDR, and show that intravitreal anti‐VEGF treatment causes increased fibrosis in PDR patients. These findings provide strong support for the model that the balance of CTGF and VEGF determines the angiofibrotic switch, and identify CTGF as a possible therapeutic target in the clinical management of PDR.

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Preoperative Intravitreal Bevacizumab Use as an Adjuvant to Diabetic Vitrectomy: Histopathologic Findings and Clinical Implications

Cited by 69 publications

References 18 publications

Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography

Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography

Preoperative Timing of Intravitreal Bevacizumab Injection for Proliferative Diabetic Retinopathy Patients

A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy

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